The role of cytoskeleton protein adducing 3 in modulating epithelial-mesenchymal transition in glioblastoma

Abstract

Purpose Epithelial-mesenchymal transition (EMT) in cancer is characterized by altered cell morphology, weakened cell-cell adhesion, and increased tumor invasiveness. Cytoskeleton protein dysregulation enhances EMT but its translational significance in the pathogenesis of glioblastoma multiforme (GBM), a highly invasive form of malignant brain tumor, is not known. Adducin 3 (ADD3) is a major cytoskeleton protein in glioma cells. Our preliminary studies revealed significant downregulation of ADD3 in GBM, and provided the first in vivo evidence on the putative tumor suppressive role of ADD3 in modulating GBM growth and angiogenesis. We aim to interrogate the translational potential of ADD3 as a therapeutic target and to unravel the molecular mechanisms underlying EMT induction in GBM. Methods To better recapitulate the disease-relevant tumor environment, GBM cells will be studied in an ECM-enriched culture system in vitro and in animal-based models. Cells will be cultured and maintained in fibronectin-coated plates. Results It was found that ADD3 loss-of-function promote EMT phenotypes in GBM, mediated through significant changes in cellular polarity, and the focal adhesion signaling pathways that favors cancer cell migration and invasion. Conclusions The highly infiltrative behavior of GBM is an important determinant that contributes to treatment failure. It emerged that GBM is equipped to downregulate ADD3 at the genetic level to drive cytoskeletal changes that favors cell proliferation and mesenchymal phenotype. Our study revealed the molecular mechanisms on how cytoskeleton protein ADD3 renders GBM cells towards an EMT phenotype that drives cancer cell invasion in GBM